This invention relates to nutritional formulas, specifically enriched infant formulas that contain long chain polyunsaturated fatty acids (LCPs or LC-PUFAs); and to methods of using such formulas to provide enhanced neurological development in infants, specifically in infants born prematurely (xe2x80x9cpretermxe2x80x9d infants).
Whether or not formulas designed for the preterm infant should be supplemented with LCPs, including arachidonic acid (xe2x80x9cAAxe2x80x9d, 20:4n-6) and/or docosahexaenoic acid (xe2x80x9cDHAxe2x80x9d, 22:6n-3) has become one of the most controversial issues in infant nutrition today. Several lines of logic suggest that preterm infants fed infant formulas without AA and DHA may be at increased risk of sub-optimal blood and tissue levels of these fatty acids compared to the term infant. First, DHA accumulation in the brain and retina is most rapid during the last intrauterine trimester, between 25 and 40 weeks"" postmenstrual age (Clandinin, et al. 1980; Martinez, 1991) and the early months after birth (Martinez, 1991); hence, the physiologic requirement for DHA is highest during the perinatal period. Second, the supply of AA and DHA to the preterm infant may be limited due to early termination of maternal-to-fetal transfer of those fatty acids. Clandinin, et al. (1980) reported that approximately 80% of intrauterine AA and DHA accumulation occurs during the last intrauterine trimester. Third, supply may also be limited due to immature de novo synthesis of AA and DHA from their dietary essential precursor fatty acids, linoleic (18:2n-6) and xcex1-linolenic (18:3n-3) acids, respectively. While it has been shown that premature infants are capable of de novo synthesis of AA and DHA (Carnielli, et al. 1996; Salem, et al. 1996; Sauerwald, et al. 1996), it is not clear whether these enzymatic pathways are sufficient in the preterm infant to meet the requirements for AA and DHA (Carlson 1997 Indeed results of randomized controlled trials with preterm infants fed formulas containing DHA but no AA have been interpreted by some to suggest more rapid maturation of retinal physiology (Birch, et al. 1993), visual function (Birch, et al. 1993; Carlson et al 1993a, 1996a) and/or neurodevelopment. However, there are also reports of impaired or slower growth in preterm infants fed formula containing DHA but no AA. For example, Carlson, et al. (1992) found slower growth from 4 to 12 months CA, as well as depressed motor development at 12 months CA (Carlson 1993c), in preterm infants fed a preterm formula containing DHA until hospital discharge followed by a term formula supplemented with DHA until 9 months CA. A second study by Carlson, et al. (1996b) also showed slower growth. In this study, preterm infants were fed a preterm formula containing DHA to 2 months CA, and growth deficits were found at 6, 9 and 12 months CA. A third study (Ryan, et al. 1998) showed slower growth in preterm infants fed a preterm formula containing DHA for two months following hospital discharge and then a term formula containing DHA for an additional four months. Growth faltering in male infants was observed at about 3 and 5 months CA.
While early nutrition and growth can be a significant predictor of later development (Hack et al 1991; Morley and Lucas 1994), there is a lack of consensus that the improvements in visual- and neurodevelopment warrant the feeding of DHA at the expense of slower growth. Thus, there remains a need for a solution that provides improved development (visual, neurological and otherwise) without the concomitant slowed growth rate associated with prior art feeding protocols.
Carlson, et al. (1993b) hypothesized that inclusion of AA in DHA-containing formulas would correct the observations of negative growth. To the applicants"" knowledge, no prior studies have tested this hypothesis. To do so effectively, a study must examine growth well beyond 2 months corrected age (CA) as it is during this later time period (e.g. at 3, 5, 6, 9 and 12 months CA) that negative growth has been observed in previous studies (Carlson, et al. 1992, 1996b; Ryan, et al. 1999). Schade, et al in WO 98/44917 (published October 1998, claiming priority to U.S. application No. 60/042,366 dated Mar. 27, 1997) describe a study in which DHA and AA were fed to preterm infants in a fortified formula for 28 days or until hospital discharge, whichever was longer, but infants were then switched to a routine term infant formula without AA and DHA and followed only until 4 months CA. This study reports no differences in visual acuity and no adverse growth issues during or through 4 months CA following this short feeding interval. Vanderhoof, et al. (1999; 2000) report a study wherein preterm infants were fed a fortified formula supplemented with DHA and AA until term CA, then were switched to a standard formula supplemented with DHA and AA until 2 months CA. The 1999 paper reports data from the 2 months CA observations, and the 2000 (August) paper presented certain data to 12 months CA. Growth was found to be not different from the control, but reported outcomes did not include any enhanced development.
Importantly, no studies to date have examined the impact of feeding AA- and DHA-containing formula to premature infants for prolonged periods; e.g. to 6, 9 or 12-months CA, the age recommended in the absence of HM for cessation of formula feeding in term infants (American Academy of Pediatrics, 1998). Likewise, applicants"" are aware of no studies that have examined the maturation impact of feeding AA and DHA as part of a nutrient-enriched feeding regimen specifically designed for the preterm infant beyond 6-months CA. Lucas, et al. (1992) demonstrated greater linear growth and weight gain among preterm infants fed a nutrient-enriched formula to 9-months CA compared to preterm infants fed formula designed for the term infant, but neither formula contained DHA or AA.
Further, none of the studies to date have made an attempt to control for the possible confounders of home environment and maternal intelligence. Both variables can significantly influence the development of infants.
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Hence, we conducted a comprehensive randomized control trial that was adequately powered to assess the suitability and possible benefits of supplementing nutrient-enriched formulas designed for preterm infants with oils (fish/fungal or egg-DTG/fish, as defined below) containing the LCP""s AA and DHA. These nutrient-enriched, LCP-containing formulas were fed for a prolonged period beyond 6-months corrected age; in fact to 12-months corrected age.
There are several aspects of the present invention, each of which is described in a subsection below. Any aspect may occur in combination with any other aspect. Terms used in this summary are defined elsewhere in this application.
A first aspect of the invention relates to an improved method of providing nutrition to a preterm infant, comprising feeding the infant a nutrient-enriched formula for an extended period, i.e. until at least 6 months CA and preferably until 9 or even 12 months CA. Preferably, the nutrient-enriched formula is supplemented with LCPs, specifically AA and DHA at levels discussed herein. Such feeding regimens may be the exclusive source of caloric intake for the infant, or they may be complemented with human milk initially, and/or with solid foods at later stages, e.g. after about 2 to 4 months CA. In a preferred variation, the method comprises feeding the infant according to a staged regimen, using a Type I nutrient-enriched formula containing DHA and AA until the infant reaches hospital discharge or about term corrected age (xe2x80x9cCAxe2x80x9d), followed by a Type II nutrient-enriched formula containing DHA and AA until the infant reaches at least 6 and preferably 9 or 12 months CA. Feeding regimens such as those described in the above paragraph may be referred to as xe2x80x9ccatch-upxe2x80x9d feeding regimens, referring to the enhanced neurological development discussed below. A major advantage of such feeding regimens over the prior art is that they do not exhibit the growth inhibition that was previously observed when DHA without AA was fed.
A second aspect of the invention provides for improved or enhanced neurological development of preterm infants by feeding said infant a nutrient-enriched formula containing DHA and AA until the infant reaches at least 6 months CA. Enhanced neurological development is assessed herein as visual development, motor development and/or language development, each discussed below, as compared to infants not receiving comparable nutrient-enriched formula containing DHA and AA until the infant reaches at least 6 months CA. The feeding until the infant reaches at least 6 months CA may consist of exclusively formula, formula plus human milk, or, after about 2 to 4 months CA, it may include supplemental solid food.
Visual Development
An aspect of the invention is a method for improving the visual development of a preterm infant comprising feeding said infant a nutrient-enriched formula containing DHA and AA until the infant reaches at least 6 months CA. Visual development may be measured by any of several techniques, including Teller Acuity cards, Visual Evoked Potential (xe2x80x9cVEPxe2x80x9d) Acuity and VEP Contrast Sensitivity, as described herein. While some investigators have fed DHA in the prior art and found enhanced visual development, this benefit has been associated with lower growth rates in preterm infants and has caused concern among some investigators about the rationale for adding DHA to infant formulas. In fact, while some countries permit the addition of LCPs to formula, they are still prohibited by the regulatory agencies in the US and Canada, presumably due to safety concerns. The present invention overcomes this problem by demonstrating improved visual development without compromising growth.
Preferably according to the invention, DHA and AA are present in amounts and ratios discussed herein and they are fed in nutrient-enriched formulas, for an extended regimen.
Motor Development
Another aspect of the invention resides in a method for enhancing or accelerating the motor neuro-development of a preterm infant, comprising feeding said infant a nutrient-enriched formula containing DHA and AA until the infant reaches at least six months CA, preferably until nine or even 12 months CA. This method appears to be most evident in small preterm infants having birthweights of less than about 1400 g, preferably less than about 1250 g. It may be preferable to feed preterm infants according to a staged extended regimen as described above. The present invention overcomes the prior art problem by demonstrating the improved motor development without compromising growth.
Language Development
Another aspect of the invention resides in a method for enhancing or accelerating the language development of a preterm infant, comprising feeding said infant a nutrient-enriched formula containing DHA and AA until the infant reaches at least six months CA, preferably until nine or even 12 months CA. It may be preferable to feed preterm infants according to a staged extended regimen as described above. The present invention overcomes the prior art problem by demonstrating the improved language development without compromising growth.
Another aspect of the invention is a nutritional composition, such as an infant formula, containing DHA and AA, and their respective precursor essential fatty acids alpha-linolenic acid (ALA) and linoleic acid (LA), in amounts that produce the beneficial effects seen from the present formulas. Through the comprehensive study underlying this invention, it has surprisingly been discovered that much lower levels of DHA and AA may be used in infant formulas to gain the beneficial effects without compromising anthropometric growth. The advantages of lower levels are at least two-fold: First, in view of the growth and safety concerns with DHA and AA noted in the literature, prudence mandates that one add only as much of these LCPs as is necessary to achieve the desired advantages. Second, as these LCP oils are relatively expensive and add significantly to the cost of infant formulas, one should again add only what is necessary. Specific variations of this composition and its use to provide nutrition to preterm infants are discussed herein.